1-[pyrido(3,4-b) -1,4-oxazin-4-yl] -1h-indoles, the retrieval method, composition and derived n-(4 - pyridinyl)-1h-indol-1-amine

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds as substances with healing disorder memory capacity and/or with antidepressant activity. The inventive product 1-[pyrido[3,4-b] 1,4-oxazinyl-4-yl] -1H indoles f-ly, R1-H, R2-H or lower alkyl, R H, HE, benzyloxy or a group of f-crystals 2, where R4-H, R5lower alkyl. Composition, Balausa restoring memory loss activity and/or having antidepressant activity, contains compound 1 as an effective oral, parenteral or internal dose of up to 1 to 100 mg per kg of body weight per day. Compound 1 is obtained by cyclization of compound 3 in the presence of a strong base. 4 C. and 5 C.p. f-crystals. Connection structure of f-crystals 1, 2, 3: (see below ). 1 Il.

The invention relates to compound I of the formula

(I) where R1hydrogen;

R2hydrogen or lower alkyl;

R3hydrogen, hydroxy group, gasoline, lexi-group or group-O--NR4R5where R4hydrogen; R5lower alkyl.

Compounds according to the invention are suitable for alleviating depression or different RA is the invention relates also to compounds of the formula

(II) where R1hydrogen;

R2hydrogen or lower alkyl;

R3hydrogen or benzyloxy group;

X represents halogen;

R7is a group (CH2)2HE.

These compounds are useful as intermediates in obtaining the target compounds.

Unless specified or indicated otherwise, throughout the description and the attached claims will apply the following definitions.

The term lower alkyl refers to linear or branched alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and linear and branched pentyl, hexyl and heptyl.

The term halogen means fluorine, chlorine, bromine or iodine.

Throughout the description and the attached formula isoberlinia given chemical formula or name shall encompass all stereo, optical, geometric and tautomeric isomers, where such isomers exist.

Compounds according to the invention receive the following way.

If not specified or not specified, the substituents R1, R2, R3, R4and RCyclization using strong bases, such as sodium hydride or tert-piperonyl potassium, receiving compound I, where R3is hydrogen.

This reaction is usually carried out in a polar aprotic solvent such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrolidone, hexamethylphosphoramide or dimethylsulfoxide, at a temperature of approximately 25-100aboutWith for about 1-10 hours

If necessary, the compound of formula I, where R3benzyloxy, is subjected to catalytic hydrogenolysis to obtain the compounds of formula I in which R3hydroxy group.

The hydrogenolysis is usually carried out in the presence of a catalyst based on a noble metal such as platinum or palladium on carbon, in the lower alkanol, such as ethanol or isopropanol, at a temperature of approximately 25-80aboutC.

If necessary, the compound in which R3hydroxy group, is introduced into reaction with the isocyanate of formula R5-NCO, where R5represents a lower alkyl, a semi - tea compound I, where R3is a group-O--other5.

This reaction is usually carried out in the presence of a base such as potassium carbonate, in a solvent such as tetrahydrofuran, when the tempo is of suitable for the treatment of various memory disorders, characterized by decreased cholinergic or adrenergic function, such as Alzheimer's disease, and to alleviate depression.

Such use follows from the ability of these compounds to inhibit the enzyme acetylcholinesterase, thereby increasing acetylcholine in the brain.

Test for inhibition of cholinesterase.

Cholinesterase find all over the body as in mind. and in serum. However, only the distribution of acetylcholinesterase (hE) in the brain is correlated with the Central cholinergic innervation. The same innervation, as suggested, is attenuated in patients suffering from Alzheimer's disease. We determined the inhibition of in vitro acetylcholinesterase activity in the striatum of the rat in accordance with the procedure described below.

Inhibition of in vitro acetylcholinesterase activity in the striatum of the rat.

The acetylcholinesterase (hE), which is sometimes nazyvyut istennoy or specific cholinesterase, found in nerve cells, skeletal muscle, smooth muscle, various glands and erythrocytes. 'ache. May differ from other cholinesterase specificnosti on the substrate of the Oia. A clear fractionation shows the highest level in the nervous system.

Usually consider that the physiological role of AChE is the rapid hydrolysis and inactivation of acetylcholine. The AChE inhibitors are characterized by a noticeable halymeniaceae effects in holinergiceski innervated effector organs and in treatment, their use in the treatment of glaucoma. infants and paralytic ileus. In recent studies, however, it has been suggested that AChE inhibitors can also be used successfully in the treatment of dementia caused by Alzheimer's disease.

Described below is the method used in the present invention for the analysis of anticholinesterase activity. It represents a modification of the method proposed by Almana and others in Biochem. Pharmacol. 7, 88, (1961).

Technique

A. Reagents

1. 0.05 M phosphate buffer, pH 7.2

(a) 6.85 g NaH2PO4H2O (100 ml of distilled H2ABOUT

(C) 13,40 g Na2HPO47H2O/100 ml distilled H2ABOUT

(C) add (a) to (C) up until the pH reaches of 7.2 (d) dilute at a ratio of 1:10.

2. The substrate in the buffer

(a) 198 mg acetylthiocholine (10 IMO is to 19.8 mg of 5,5-dithiobisnitrobenzoic acid (DTNB),(0.5 mmol)

(C) bring to 100 ml with 0.5 M phosphate buffer, pH 7.2 (reagent 1).

4. To prepare 2 mm basic solution of the test drug in a suitable solvent and dilute to volume with 0.5 mm DTNB solution (reagent 3). Then the drugs sequentially diluted (1: 10) so that the final concentration (in a ditch) was 10-4M, and screening for activity. If the activity has, according to the activity of the inhibitor in serial concentrations are determined by the value of the IC50.

C. Preparation of tissue.

Male rats of the form "Wistar" decapitate, quickly remove the brain, unleash striped body, weighed and homogenized in 19 volumes (approximately 7 mg protein/ml) in 0.05 M phosphate buffer pH 7,2, by using a homogenizer (Potter-Alaama. An aliquot of homogenizate in 25 μl added to 1 ml of the medium or various concentrations of the test drug and pre-incubated for 10 min at 37aboutC.

C. Analysis.

Enzyme activity was measured using spectrophotometer model Beckman DU-50". This method can be used to estimate the IC50and to measure the>Program 6 Kindata:

Source Vis

The wavelength of 412 nm

Zipper is missing

Cuvette 2 ml cuvettes with automatic six-time dosing

A blank experiment 1 for each substrate concentration.

The period of time of 15 s (15 or 30 s for kinetics)

Total time of 5 minutes (5 or 10 min for kinetics)

Schedule

The range of automatic scale selection

The slope of the increasing

Results Yes (given the slope)

Factor 1

The reagents in the cuvette for idle and experience in the cuvette with the sample type as follows: Single experience of 0.8 ml phosphate

buffer (DTNB

0.8 ml buffer)substrate Control: 0.8 ml phosphate

buffer (DTNB) fer-

COP

0.8 ml phosphate

buffer/substrate Medicine: 0.8 ml phosphate

buffer (DTNB) pharmaceutical-

CTB/enzyme

0.8 ml phosphate

buffer/substrate

Values for empty cuvettes determined in each experiment to control nonenzymatic hydrolysis of the substrate. These m values are automatically deducted using Kindata programs available in the software module soft-RAS to calculate kinetics. This program also calculates the rate of change in absorbance for each cuvette.

100

In table. 1 presents the results of this analysis for some of the compounds according to the invention, and physostigmine (reference compound).

The usefulness of the compounds of the present invention are further demonstrated their ability to recover holinergiceski insufficient memory in the following test on the avoidance of darkness.

The test for the avoidance of darkness.

In this test, mice are tested for their ability to remember an unpleasant stimulus within 24 hours the Mouse is placed in a chamber which has a dark compartment; a very bright light chases the mouse in this dark compartment, where through the metal plates on the floor of the mouse result in a state of shock. The animal is removed from the apparatus for a test and test again 24 hours later on the ability to remember the electric shock.

If the animal back to its original premises in the test chamber is injected scopolamine, an anticholinergic agent, which is known to cause weakening of memory, the animal re-enters the dark compartment shortly after it is placed in the test chamber later is m ore than a long period of time before re-entry into the dark compartment.

The results for active compounds is expressed as the percent of animals that have blocked the effect of scopolamine, which is manifested in a larger interval between the location of the animal in the test chamber and its re-entry into the dark compartment.

In table. 2 presents the results of this test for some of the compounds according to the invention, for tacrine and policarpio (reference compound).

The purpose of these connections entities in need of improving memory, perform as an effective oral, parenteral or intravenous dose comprising about 1-100 mg/kg of body weight per day. Especially effective combined amount of about 10 mg/kg of body weight per day. It should be understood that for any particular subject, specific regimen of the medicinal product must be installed in accordance with the individual needs of the patient and the professional recommendation of a specialist, who will appoint or control the introduction of the above-mentioned compounds. In addition, specified doses are only examples and in no way limit the scope or practice of the present invention.

Absorption

Neural mechanism of reuptake of norepinephrine (NE) is the most important physiological way of inactivation of NE by removal of neurotransmitter from the synaptic cleft. Absorption NE by using saturable, stereospetsifichno with high affinity, and is dependent on active sodium transport system, which has been shown to exist both in peripheral tissues and the Central nervous system. Absorption NE strongly inhibited by cocaine, phenethylamine and tricyclic antidepressants. It also inhibit ouabain, metabolic inhibitors and phenoxybenzamine. Inhibition of the uptake of NE using clinically effective tricyclic antidepressants is an important link in the catecholamine hypothesis of effective disorders, and there was extensive correlation of activity patterns and absorption NE.

There are large regional variations in the uptake of NE, which is correlated with the endogenous levels of NE. The hypothalamus is characterized by the highest level of NE and greatest absorption. Synaptosomal uptake of3N-NE predom on connection which potentiate the effect of NE by blocking mechanism of re-absorption.

Method.

A. Animals: male rats of the form "CR Wistar" (100-125 g)

C. Reagents

1. Bicarbonate buffered Krebs-Henseleit, pH=7,4 (CNW).

Prepare 1 liter of the bath containing the following salts:

NaCl 6,92 118,4 KCl 0,35 4,7 MgSO47H2O 0,29 2,2 NaHCO32,10 24,9 CaCl20,14 1,3

Before use add: Dextrose 2 mg/ml 11,1 Iproniazid phosphate 0.30 mg/ml 0.1

Aeronaut for 60 min with a mixture of 95% O2and 5% CO2check pH (7,40,1).

2. of 0.32 M Sucrose: of 21.9 g of sucrose, adjusted to 200 ml.

3. Prepare 0.1 mm basic solution of L(-)-norepinephrine of bitartrate in 0.01 N HCl. It is used to dilute the specific activity of NE-labeled radioactive label.

4. Left-(cycle-2,5,6-3H)-norepinephrine[40-50 Ku/mol] receive from the company "New England Nuclear".

The final desired concentration3N-NE in this analysis is 50 nm. The dilution ratio is equal to 0.8. Therefore, CNW prepared so that it contained at 62.5 nm (3N) IS A NE.

Add 100 ml CNW:

A. 59,4 ál of 0.1 mm NE 59,4 nm

*Century 0.31 nmol3N-NE of 3.1 nm

at 62.5 nm

x) Added to the Noi solution of the test compound is prepared in a suitable solvent and serially diluted so so that the final concentration in the analysis was in the range from 2 to 10-8up to 2 10-5M In each analysis using seven concentrations. Depending on the effectiveness of the tested compounds may be used in higher or lower concentration.

C. Preparation of tissue.

Male rats of the form "Wistar" decapitate and quickly remove the brain. Weigh or whole brain without cerebellum or the hypothalamus and homogenized in 9 volumes of 0.32 M sucrose, cooled in an ice bath, by using a homogenizer (Potter-Alaama. Homogenization should be done with 4-5 moves up and down at medium speed to decrease to the limit lysis by synaptosomes structures. Homogenized centrifuged at 1000 g for 10 min at 0-4aboutC. Insufficient fluid (S1) decanted and used in the experiments on the uptake.

D. Analysis

800 ál KNW containing (3N)-NE

20 μl of Media or the appropriate concentration of drug

200 µl of the Suspension fabric

The tubes are incubated at 37aboutC in an atmosphere of 95% O2and 5% CO2within 5 minutes For each analysis incubated for 3 tubes with 20 ml of the medium at 0aboutC in an ice bath. After incubation all tubes it is the group of 1 ml of solubilizer (Triton X-100 + 50% ethanol, 1:Ob./vol.). The tubes vigorously shaken in a circular motion, decanted into scintillation vials and produce counting in 10 ml of a liquid mixture for scintillation counting. The active acquisition represents the difference between the number of counts per minute at 37 and 0aboutC. the Percentage of inhibition for each concentration of the drug is the average of three determinations. The magnitude of the inhibitory concentration (IC50) derive, using the logical test analysis.

The results of this test are presented in table. 3.

The results of the trials ' Primary Overt Effects obtained in rats, for compounds of example Id showed that at a dose of 80 mg/kg (intraperitoneal introduction), no rat did not die, which suggests that the toxicity of the compounds according to the invention is above 80 mg/kg

Effective amounts of compounds according to the invention, can be assigned for administration to a subject by any known methods, for example orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. Compounds according to the invention, being effective are lisali, increased solubility and the like.

Acids suitable for the production of pharmaceutically acceptable salts according to the invention are inorganic acids such as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric and perchloric acid and organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.

The active compounds according to the invention can be administered orally, for example, with an inert diluent or with an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration compounds can be mixed with excipients and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5% of active compound but the number may vary depending on the particular form and, mainly, may lie in the range from 4 wt. to about 75 wt. on the input unit. The number present in such compositions connection is such that it must be ensured that eligible the actual dosage unit form contains from 1.0 to 300 mg of active compound.

Tablets, pills, capsules, lozenges and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose, disintegrity agent, such as alginic acid, Primogel", cornstarch and the like; lubricating agent such as magnesium stearate or Sarotex", sliding additive such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring, such as peppermint, methyl salicylate or substance with a smell of orange. When the dosage unit form is a capsule, it is in addition to the above substances may contain a liquid carrier such as fatty oil. Other dosage unit forms can contain various other substances, which modify the physical form of the dosage unit, such as coating. Thus, tablets or pills may be coated with sugar, shellac or other intersolubility shells. Syrup, in addition to the active compounds, may contain sucrose as a sweetening agent and certain preservatives, gracebyte pharmaceutically pure and necozione in the applicable quantities.

For the purpose of parenteral therapeutic introduction of the active compounds according to the invention can be put into solution or suspension. These preparations should contain at least 0.1% of the above-mentioned compounds, but can vary from 0.5 to about 30% by weight of the preparation. The number of active compound in such compositions is such that it will be suitable dose. Preferred compositions and preparations according to the invention is prepared so that parenterally dosage unit contains from 0.5 to 100 mg of active compound.

The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl ester of para-aminobenzoic acid; antioxidants such as ascorbic acid or sodium bisulfite; hepatoblastoma agents, such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate or phosphate, and agents for adjusting toychest, such as Haakon with multiple doses, manufactured from glass or plastic.

The following are examples of typical pharmaceutical formulations based on the compounds of the invention.

The tablets. The ingredients In each tablet-

letke, mg Active ingredient 300 Polyvinyl pirrolidone 22.5 Lactose 61,75 Alcohol 3A 200-th sample of 4.5 Stearic acid 9 Talc 13,5 Corn starch 43,25

Mix the active connection, polyvinylpyrrolidone and lactose together; pass through a sieve of 40 mesh. Slowly add the alcohol and mix well. Miss wet mass through a sieve 4 mesh. Dry the granules at 50aboutWith during the night. The dried granulate is passed through a 20 mesh. Sift stearic acid, talc and corn starch through a sieve of 60 mesh before mixing in the drum with the granulate. Pressed using standard 7/16-inch concave punch. 10 tablets should weigh 4,5,

Candles: the Ingredients In each

the candle mg of Active ingredient 300 Glycerin 3000 Purified water 200

Glycerin is heated in a suitable vessel until the 120aboutC. the Drug is dissolved with gentle stirring, and then heated glycerin is added purified water and mix. The hot mixture is immediately poured into the appropriate form.

Apart, 30 ml Oil 250 ml Purified water, ml to 500

* derived from the acid-treated precursor; used at pH of 3.2.

Add gelatin and medicine to about 300 ml of purified water, allow to stand a few minutes, then heated to dissolve the gelatin, after which the temperature was raised to 98aboutC and maintained at this temperature for about 20 minutes, Cooled to 50aboutTo add flavor, alcohol and purified water in a quantity sufficient to obtain 500 ml Add oil, mix thoroughly with the mixture and pass it through a homogenizer or kolodney mill up until the oil is fully and evenly dispersed.

Examples of compounds according to the invention: N-(3-foroperation-4-yl)-N-(3-methyl-1H-indol-1-yl)-1-aminoethanol;

N-(3-foroperation-4-yl)-N-(1H-indol-1-yl)-2-aminoethanol;

4-(3-methyl-1H-indol-1-yl)-pyrido[3,4-b] 1,4-oxazin; N-(3-fluorescent-4-pyridyl)-N-(5-benzilic-si-1H-indol-1-yl)-2-aminoethanol;

4-(1H-indol-1-yl)-pyrido[3,4-b]-1,4-OK - satin;

4-(5-benzyloxy-1H-indol-1-yl)-Piri-up[3,4-b] 1,4-oxazin;

1-(pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-ol;

1-(pyrido-[3.4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-methylcarbamate;

1-(pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-meth is ndol-5-yl-1,2,3,4-tetrahydrothieno Il - 1-(pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-isopropylcarbamate; 1-(pyrido[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-fenilmetilketenom;

1-(pyrido-[3,4-b] 1,4-oxazin-4-yl)-3 - ethyl-1H-indol-5-yl-piperidinylcarbonyl; 1-(pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-morrisonicola; 1-(pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-4-methylpiperazine 1-(pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-4-phenylethylhpiperidinyl bamat;

N-(3-fluorescent-4-pyridinyl)-N-(1H-indol-1-yl)glycine ethyl ester;

N-(3-foroperation-4-yl)-N-(1H-indol-1-yl)-2-aminoethanol;

4-(1H-indol-1-yl)-pyrido[3,4-b]-1,4-OK-satin;

N-(3-chloro-4-pyridinyl)-N-(5-Benzino - XI-1H-indol-1-yl)glycine ethyl ester;

N-(3-chloro-4-pyridinyl)-N-(5-Benzino - XI-1H-indol-1-yl)-2-aminoethanol;

ethyl ester of N-(3-fluorescent-4-pyridinyl)-N-(5-benzyloxy-2-methyl-1H-indol-1-yl)glycine;

N-(3-fluorescent-4-pyridinyl)-N-(5-Benzino - XI-2-methyl-1H-indol-1-yl)-2-aminoethanol;

4-(5-benzyloxy-2-methyl-1H-indol-1 - yl)-pyrido[3,4-b] 1,4-oxazin;

2-methyl-1-(pyrido[3,4-b] 1,4-oxazin-4 - yl)-1H-indol-5-ol;

2-methyl-1-(pyrido[3,4-b] 1,4-oxazin - 4-yl)-1H-indol-5-yl-methylcarbamate;

2-methyl-1-(pyrido[3,4-b] 1,4-oxazin - 4-yl)-1H-indol-5-yl/fenilmetilketenom;

N-(3-fluorescent-4-pyridinyl)-N-(5-methoxy - 1H-indol-1-yl)2-aminoethanol;

4-(5-methoxy-1H-indol-1-yl)-pyrido[3,4-b] 1,4-oxazin;

N-(3-fluorescent-4-pyrimidinyl)-N-(6-chloro-1H-indol-1-yl)-2-aminoethanol; and

4-(6-chloro-1H-indol-1-yl)-pyrido[3,4 - b] 1,4-oxazin.

The following examples illustrate the purposes and should not be construed as limiting the invention. Unless otherwise indicated, all temperatures are given in degrees Celsius (aboutC).

P R I m e R Ia. N-(3-Fluorescent-4-pyridinyl)-3-methyl-1H-indol-1-amine.

To 200 ml of isopropanol added 4-hero-3-foroperational (10 g) and 3-methyl-1H-indol-1-amine (5.9 g). The mixture peremeshyvaet 90aboutC for 4 h, cooled; then poured into 500 ml of ice water; the pH with a solution of Na2CO3cook until 10, then extracted with ethyl acetate. The organic layer is washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtration the solvent is evaporated to a oil which aluinum on a column of silica gel with CH2CL2(DCM) and then with a mixture of diethyl ether:petroleum ether (1: 1) using column chromatography. The target fractions are combined and then evaporated, obtaining 6.2 g of solid product, 45aboutC. a Sample of this substance is recrystallized in the system: isopropyl ether:hexane (1:1), separating the solid product with a melting point 141-142aboutC.

Elemental analysis:

Races is about-4-pyridinyl)-N-(3-methyl-1H-indol-1-yl)glycine ethyl ester.

To a suspension of NaH (60% in oil, 1.48 g) in 10 ml of dimethylformamide (DMF) at a temperature of the ice bath is added dropwise a solution of N-(3-fluorescent-4-pyridinyl)-3-methyl-1H-indol-1-amine (8.5 g) in 40 ml DMF. After complete addition, the mixture peremeshyvaet for 15 min at the temperature of the ice bath and then cooled to -20aboutC. added dropwise ethylchloroformiate (3,95 ml) in 10 ml of DMF. The mixture is stirred at -20aboutC for 1 h Then the mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried (saturated NaCl, anhydrous MgSO4). After filtration, the solvent evaporated, receiving oil (12.2 g) which is purified by high performance liquid chromatography on a column of silica gel, elwira with a mixture of 10% ethyl acetate and SEE. The target fraction evaporated, releasing of 6.9 g of solid substance with a melting point 105-108aboutC.

Elemental analysis:

Calculated for C18H18FN3O2: C 66,04% N 5,54% N 12,84%

Found: of 66.00% H of 5.53; N 12,81%

P R I m e R Ic. N-(3-Foroperation-4-yl)-N-(3-methyl-1H-indol-1-yl)-2-aminoethanol.

To ethyl ether, N-(3-fluorescent-4-pyridinyl)-N-(3-methyl-1H-indol-1-yl)glycine (5.0 g) in 100 ml of tetrahydrofuran, cooled to the temperature of the ice bath, the syringe EXT PM The mixture is cooled rapidly with NH4Cl and extracted three times with ethyl acetate. The organic fractions combined, washed with saturated NaCl and dried (MgSO4). After filtration, the solvent evaporated, releasing solid (3.9 g) which is purified by liquid chromatography high pressure (NRS) on a column of silica gel, elwira a mixture of 50% ethyl acetate and dichloromethane. The target fraction evaporated, highlighting 3.7 g of the solid product with a melting point of 123-125aboutC.

Elemental analysis:

Calculated for C16H16FN3O: 67,35% N 5,65; N 14,73%

Found: 67,45% N 5,67% N 14,72%

P R I m e R Id. 4-(3-Methyl-1H-indol-1-yl)-pyrido[3,4-b] 1,4-oxazin.

To a suspension of NaH (0.34 g) in 5 ml of dimethylformamide added N-(3-foroperation-4-yl)-N-(3-methyl-1H-indol-1-yl)-2-aminoethanol (2.0 g) in 50 ml of dimethylformamide. The reaction mixture is heated to 70aboutC and stirred for 4 h the Mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried (saturated NaCl, MgSO4). After filtration, the solvent evaporated, releasing oil (2.8 g) which is purified by liquid chromatography high pressure on a column of silica gel, elwira a mixture of 50% etilatsetata/dichloromethane>Elemental analysis:

Calculated for C16H16N3O: 72,43% N 5,70% N 15,48%

Found: 72,37% N 5,74; N 15,76%

P R I m e R 2A. N-(3-Fluorescent-4-pyridinyl)-N-(5-benzyloxy-1H-indol-1-yl)-2-amino - ethanol.

To a solution of ethyl ester of N-(3-fluorescent-4-pyridinyl)-N-(5-benzyloxy-1H-indole- -1-yl)glycine (18.7 g) in 100 ml of tetrahydrofuran, cooled to a temperature of an ice bath, is added dropwise sociallyengaged (89,16 ml). The solution is stirred for 0.5 h, then cooled rapidly using ammonium chloride and extracted with ethyl acetate. The organic layer is washed with water and dried (saturated NaCl, MgSO4). After filtration, the solvent evaporated, releasing solid (12.5 g) which is purified by liquid chromatography high pressure on a column of silica gel, elwira a mixture of 50% ethyl acetate/dichloromethane. The target fraction evaporated, getting 9,65 g of solid substance with a melting point of 130-132aboutC.

Elemental analysis:

Calculated for C22H20FN3O2: 70,01% H 5,34% N 11,13%

Found: 69,98% N 5,28% N 11,04%

P R I m e R 2V. 4-(5-Benzyloxy-1H-indol-1-yl)-pyrido-[3,4-b] 1,4-oxazin.

Sodium hydride (1.0 g) suspendre in dimethylformamide (10 ml). This mixture is cooled(to 8.25 g) in 100 ml of dimethylformamide, and the reaction mixture is heated to 70aboutC and stirred for 3 hours the Mixture is cooled, poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried (saturated NaCl, anhydrous MgSO4). After filtration, the solvent evaporated, releasing a solid product (12.2 g) which is purified by liquid chromatography high pressure on a column of silica gel, elwira a mixture of 50% ethyl acetate/dichloromethane. The target fraction evaporated, receiving of 7.4 g of solid, which triturated with diethyl ether, highlighting of 4.04 g of the solid product with a melting point 181-183aboutC.

Elemental analysis:

Calculated for C22H19N3O2: 73,93% N ARE 5.36% N 11.75% PER

Found: 73,67% N 5,39% N 11,68%

P R I m e R 3. 1-(Pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-ol.

4-(5-Benzyloxy-1H-indol-1-yl)-Piri-to-[3,4-b] 1,4-oxazin (5.0 g) in 240 ml of ethanol is added to a suspension of 10% Pd/C (0.6 g) in 10 ml of ethanol. This mixture hydrogenizing in a Parr apparatus for 2 h at 50aboutC. Then the mixture is cooled, filtered and the filtrate is evaporated, releasing solid (3.5 g). This product is purified by liquid chromatography high pressure on a column of silica gel, elwira mixture of 5% methanol/dig the recrystallization from acetonitrile, getting to 0.62 g of solid substance with a melting point 221-222aboutC.

Element analysis:

Calculated for C15H13N3O2: 67,40% N 4,90% N 15,72%

Found: 67,38% N 4,85% N 15,68%

P R I m e R 4. 1-(Pyrido-[3,4-b] 1,4-oxazin-4-yl)-1H-indol-5-yl-methylcarbamate.

Potassium carbonate (1.3 g) are added to a solution of 1-(pyrido-[3.4-b]-1,-oxazin-4-yl)-1H-indol-5-ol (2.0 g) in 100 ml of tetrahydrofuran. After stirring at room temperature for 10 min dropwise added methyl isocyanate (0,46 g). The reaction mixture was kept at room temperature for 1 h Then the mixture is filtered and the filtrate is evaporated, releasing a solid product (2.8 g). This substance is purified by liquid chromatography high pressure on a column of silica gel, elwira mixture of 5% methanol/dichloromethane. The target fraction evaporated, obtaining 3.2 g of solid, which is recrystallized from acetonitrile, highlighting 1.5 g of the solid product with a melting point 196-198aboutC.

Elemental analysis:

Calculated for C17H16N4O3: 62,95% N EQUAL TO 4.97% N 17,28%

Found: 62,95% N 4,91% N 17,30%

P R I m e R 5A. Ethyl ester of N-(3-fluorescent-4-pyridinyl)-N-(1H-indol-1-yl)glycine.

To suspensions)-1H-indol-1-amine (19 g) in 120 ml of dimethylformamide, and the resulting mixture was stirred at 0aboutFor 20 minutes After cooling the mixture to -20aboutWith over 15 min add solution ethylchloroformiate (9.6 ml) in 25 ml of dimethylformamide. The resulting mixture was stirred at -20aboutC for 1 h

The mixture is then poured into 400 ml of water, stirred for 5 min and then extracted with ethylcatechol. The organic layer is washed with water and saturated NaCl, then dried over anhydrous MgSO4.

After filtration, the solvent evaporated, getting the product in the form of oil (26 g), which is subjected to liquid chromatography high pressure on a column of silica gel, elwira a mixture of 10% ethyl acetate/dichloromethane. The target fractions are combined and then evaporated, highlighting 13.3 g of atalogo ester of N-(3-fluorescent-4-pyridinyl)-N-(1H-indol-1-yl)glycine in the form of a solid substance with a melting point 86-87aboutC.

Elemental analysis:

Calculated for C17H16FN3O2: 65,16% N 5,15% N 13,41%

Found: 65,00% N 5,14% N 13,19%

P R I m e R 5V. N-(3-Foroperation-4-yl)-N-(1H-indol-1-yl)-2-aminoethanol.

To a solution of sociallyengaged (1 M solution, 70 ml), cooled to 0aboutWith over 30 min add solution EV for 1 h at 0aboutWith add dissolve ammonium chloride, and then 300 ml of diethyl ether. The mixture is filtered. The filtrate is evaporated to give 10 g of solid, which is subjected to liquid chromatography high pressure on a column of silica gel, elwira a mixture of ethyl acetate:dichloromethane (1: 1). The target fractions are combined and then evaporated, receiving of 6.1 g of N-(3-foroperation-4-yl)-N-(1H-indol-1-yl) -2-aminoethanol in the form of a solid substance with a melting point of 133-135aboutC.

Elemental analysis:

Calculated for C15H14FN3O: 66,41% N 5,20% N 15,49%

Found: 66,33% N 5,22% N 15,41%

P R I m e R 5s. 4-(1H-Indol-1-yl)-pyrido[3,4-b] 1,4-oxazin.

To a suspension of sodium hydride (0.8 g) in 10 ml of dimethylformamide add a solution of N-(3-foroperation-4-yl-)-N-(1H-indol-1-yl)-2-aminoethanol (4.8 g) in 100 ml of dimethylformamide. After stirring at 70aboutC for 4 h the mixture was poured into 300 ml of ice water, stirred for 5 min, then extracted with ethyl acetate. The organic layer is washed with water, then saturated NaCl solution and then dried over anhydrous MgSO4.

After filtration, the solvent evaporated, getting the product in the form of oil, which is subjected to liquid chromatography high pressure column with stantsii viscous oil, which solidifies upon standing, giving 3.4 g of 4-(1H-indol-1-yl)-pyrido[3,4-b]-1,4-oxazine in the form of a solid substance with a melting point 108-110aboutC.

Elemental analysis:

Calculated for C15H13N3O: 71,70% N TO 5.21% N 16,72%

Found: 71,38% N 4,91% N 16,52%

1. 1-[Pyrido-(3,4-1,4-oxazinyl 4 yl]-1H-indoles of General formula I

< / BR>
where R1hydrogen;

R2hydrogen or lower alkyl;

R3hydrogen, the hydroxy-group, benzyloxy or group

< / BR>
where R4hydrogen;

R5lower alkyl.

2. Connection on p. 1, wherein R1the hydrogen.

3. Connection on p. 2, wherein R3hydrogen, the hydroxy-group, benzyloxy or a group of the General formula

< / BR>
where R5lower alkyl.

4. Connection on p. 1, characterized in that it is composed of 1-[pyrido(3,4-b)-1,4-oxazin-4-yl]-1H-indol-5-illecillewaet.

5. Connection on p. 1, characterized in that a represents a 4-(3-methyl-1H-indol-1-yl)-pyrido(3,4-b-1,4-oxazin.

6. Connection on p. 1 with restoring the defective memory capacity and/or with antidepressant activity.

7. The composition of the firm, containing a derivative of indole and pharmaceutically acceptable carrier, characterized in that as a derivative of indole it contains 1-[pyrido(3,4-b)-1,4-oxazin-4-yl]-1H-indole of General formula I:

< / BR>
where R1hydrogen;

R2hydrogen or lower alkyl;

R3hydrogen, the hydroxy-group, benzyloxy, or a group of the General formula

< / BR>
where R4hydrogen;

R5lower alkyl,

as an effective oral, parenteral or intravenous dose, part I 100 mg/kg of body weight per day.

8. The way to obtain 1-[pyrido-(3,4-b)-1,4-oxazin-4-yl] -1H-indoles of General formula I

< / BR>
where R1hydrogen;

R2hydrogen or lower alkyl;

R3hydrogen, the hydroxy-group, benzyloxy or a group of the General formula

,

where R4hydrogen;

R5lower alkyl,

characterized in that the compound of General formula IIB

< / BR>
is subjected to cyclization in the presence of a strong base, and if necessary, the compound of formula I, where R1and R2have the specified values, and R3benzyloxy, is subjected to catalytic hydrogenolysis to obtain a compound of formula I, where R3the hydroxy - group, or, in case the PAP, subjected to interaction with the isocyanate of General formula

R5NCO,

where R5lower alkyl,

to obtain the compounds of formula I, where R3a group of General formula

< / BR>
where R5lower alkyl.

9. Derivative (4-pyridinyl)-1H-indol-1-amine of General formula II

< / BR>
where R1hydrogen;

R2hydrogen or lower alkyl;

R3hydrogen or benzyloxy;

X is halogen;

R7group (CH2)2OH.

 

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The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

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N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

9 cl, 1 tbl, 41 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with surgical, antiseptic, antiphlogistic and wound-healing glue that contains collagen hydrolyzate, sodium salt of alginic acid, catapol, dioxidin, poviargol; additionally, it contains glycerol, nipagin, nipasol and aqueous solution of sodium hypochlorite. The innovation provides increased antimicrobial activity and regulation of biodegradation rate of covering depending upon the level of inflammatory process in the wound that leads to faster wound healing.

EFFECT: higher efficiency of application.

4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using the compound (R/S)-(-/+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or their salts for preparing a medicinal agent. This agent is used in treatment of extrapyramidal motor disorders, in particular, in treatment of unfavorable effects of anti-parkinsonic preparations and using (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman in combination with an anti-parkinsonic preparation for preparing the combined medicinal agent. Also, invention relates to a pharmaceutical composition for treatment of extrapyramidal disorders and a set of the same designation. Proposed compounds are able to prevent catalepsy caused by usual anti-dopaminergic preparations and they are strong agonists of 5-HT1A-receptors in combination with antagonism to dopamine D2-receptors and interaction with D3-receptors that provides positive effects on extrapyramidal system in treatment of dyskinesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to cyclopentyl compounds of the general formula (I): wherein X means carbon (C), nitrogen (N) or oxygen (O) atom; Y means O; Z means C; R1 means hydrogen atom, -(C0-C6)-alkyl-W-(C1-C6)-alkyl-, -(C0-C6)-alkyl-W-(C0-C6)-alkyl-(C3-C7)-cycloalkyl-(C0-C6)-alkyl wherein alkyl and cycloalkyl are optionally substituted with 1-7 independent substitutes chosen from hydroxy-group, -O-(C1-C3)-alkyl, trifluoromethyl, (C1-C3)-alkyl; W means a simple bond, -O-, -CO-, -CO2-, -CONR10- or -NR9-; R2 means -(C0-C6)-alkyl, (C0-C6)-alkyl-W-(C1-C6)-alkyl or (C0-C6)-alkyl-W-(C3-C7)-cycloalkyl wherein (C1-C6)-alkyl, (C3-C7)-cycloalkyl are optionally substituted with 1-6 substitutes chosen from halogen atom, trifluoromethyl, -(C1-C6)-alkyl; R3 means hydrogen atom, -(C0-C6)-alkyl-phenyl, -(C0-C6)-alkyl-heterocycle, -(C0-C6)-alkyl-(C3-C7)-cycloalkyl, -(C0-C6)-alkyl-CO2R10, -(C0-C6)-alkyl-(alkene)-CO2R10, -(C0-C6)-alkyl-SO3H, -(C0-C6)-alkyl-W-(C0-C4)-alkyl, -CONR10N10- or -NR10CO2R10-, -NR10-(C0-C3)-alkyl-CO2R10- wherein phenyl and heterocycle, cycloalkyl or (C0-C6)-alkyl are optionally substituted with 1-5 independent substitutes chosen from halogen atom, trifluoromethyl, hydroxy-group, (C1-C3)-alkyl, -O-(C0-C3)-CO2R10, -CN, =O, -NR10R10, -CONR10R10, -SO3-R10 or -(C0-C3)-alkyl-heterocycle and wherein phenyl can be condensed with heterocycle that the latter can be substituted with 1-2 hydroxyl groups; R4 is absent if X represents O or N, or if a double bond joints carbon atoms to which R3 and R6 are added, or R4 means hydroxy-group, -(C0-C6)-alkyl, -CN, -(C0-C3)-CO2R10; or R3 and R4 are combined and form 1H-indenyl, 2,3-dihydro-1H-indenyl, cyclopentanyl or cyclohexanyl ring wherein this obtained cycle is optionally substituted with 1-5 substitutes chosen independently from hydroxy-group, (C1-C3)-alkyl, -O-(C1-C3)-alkyl and -(C0-C3)-CO2R10; or R3 and R5, or R4 and R6 are combined and form phenyl or heterocyclic ring wherein this ring is optionally substituted with 1-7 independent substitutes chosen from hydroxy-group, (C1-C3)-alkyl, -O-(C1-C3)-alkyl, -CO2R10; R5 and R6 mean independently hydrogen atom, hydroxy-group, (C1-C6)-alkyl or (C0-C6)-alkyl-CO2R10; if Z means C then R7 means hydrogen atom, (C1-C6)-alkyl; R8 means hydrogen atom; R10 means hydrogen atom, -(C1-C6)-alkyl, benzyl, phenyl or -(C0-C6)-alkyl-(C3-C6)-cycloalkyl; n1 and n2 = 0, 1 or 2 independently and the sum n1 + n2 = 0, 1, 2 or 3; a dotted line represents a simple or double bond, and other

compounds of this series. Also, invention relates to a pharmaceutical composition modulating activity of chemokine receptors, a method for modulation of activity of chemokine receptors in mammals, and to a method for treatment, improving, regulating or decreasing risk of inflammatory and immunoregulatory disorder or disease. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

21 cl, 4 tbl, 81 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA) or (IB) given in the invention description wherein R1 means hydrogen atom, (C1-C7)-alkyl, -(CH2)n-OH, -(CH2)n-N(R6)2; R2 means (C1-C7)-alkyl, -(CH2)n-N(R6)2, -NR6C(O)C(O)O-(C1-C7)-alkyl, -NR6-(CH2)n-OH, -NR6C(O)-(C1-C7)-alkyl, -NH-benzyl; R3 means hydrogen atom or amine; or R2 and R3 in common with carbon atoms to which they are bound mean the group -N(R6)-CH2-O-CH2-; R4 means hydrogen atom or (C1-C7)-alkyl; R5 means hydrogen atom; R6 means independently of one another hydrogen atom or (C1-C7)-alkyl; R' means hydrogen atom or (C1-C7)-alkyl; n = 0, 1, 2 or 3. Also, invention relates to a medicinal agent possessing the selective blocking activity with respect of subspecies of NMDA-receptors and containing one or more compounds of the formula (IA) or (IB) or their pharmaceutically acceptable acid-additive salt or inert carrier. Invention provides preparing novel compounds possessing the high affinity to NMDA-receptors that can be used as components of a medicinal agent for treatment of diseases mediated by these receptors.

EFFECT: valuable medicinal properties of compounds and drug.

13 cl, 35 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

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